1. Field of the Invention
The invention relates to a method for expanding a population of MUC1 expressing cells.
2. General Background and State of the Art
The following documents are incorporated herein by reference: PCT Application No. PCT/US2004/027954 (WO 2005/019269), filed Aug. 26, 2004; PCT Publication No. WO 02/056022, published Jul. 18, 2002; U.S. patent application Ser. No. 09/996,069, filed Nov. 27, 2001, published as Publication No. 2003/0036199 on Feb. 20, 2003, which describe the role of MUC1 receptor in tumorigenesis.
Recent research supports the existence of cancer stem cells (CSCs) (Prospective identification of tumorigenic stem cells. Al-Hajj M, Wicha M S, Benito-Hemandez A, Morrison S J and Clarke M F. (2003). Proc. Natl. Acad. Sci. USA, 100, 3983-3988; Characterization of clonogenic multiple myeloma cells. Matsui W, Huff C A, Wang Q, Malehorn M T, Barber J, Tanhehco Y, Smith B D, Civin C I and Jones R J. (2004) Blood, 103, 2332-2336; Identification of a cancer stem cell in human brain tumor. Singh S K, Clarke I D, Terasaki M, Bonn V E, Hawkins C, Squire J and Dirks P B. (2003) Cancer Res., 63, 5281-5828). Normal stem cells are characterized by their ability to self-renew indefinitely and to differentiate to become adult cells of distinct tissue types. Progenitor cells have the ability to further differentiate into distinct cell types but have lost the ability to differentiate into any type of cell. It has been shown that not all cancer cells have the ability to self-renew, to induce disease in a new host, or to form new tumors (A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Lapidot T, Srirad C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri M and Dick J. (1994). Nature, 17, 645-648; Identification of a cancer stem cell in human brain tumor. Singh S K, Clarke I D, Terasaki M, Bonn V E, Hawkins C, Squire J and Dirks P B. (2003) Cancer Res., 63, 5281-5828; Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Bonnet D., and Dick J E. (1997) Nat. Med. 3, 730-737). Rather, only a small fraction of cancer cells have this ability to self-renew and form new tumors, i.e. metastasize. A leading theory is that cancer is caused by normal stem cells whose tightly regulated system of checks and balances has broken down (Self-renewal and solid tumor stem cells. Al-Hajj M and Clarke M F. (2004) Oncogene, 23, 7274-7282). Solid tumors occur in organs that have stem cell populations. Epithelial cancers, which include breast, prostate, colon, and lung cancers are the most common cancers in adults. Over 75% of these cancers are characterized by the aberrant expression of the MUC1 receptor (Development and characterization of breast cancer reactive monoclonal antibodies directed to the core protein of the human milk mucin. Burchell J, Gendler S, Taylor-Papadimitriou J, Girling A, Lewis A, Millis R, and Lamport D. (1987) Cancer Res., 47, 5476-5482; Monoclonal antibodies to epithelial sialomucins recognize epitopes at different cellular sites in adenolymphomas of the parotid gland. Zotter S, Hageman P C, Lossnitzer A, Mooi W and Hilgers J. (1988) Cancer Rev. 11-12, 55-101; Mucins and mucin binding proteins in colorectal cancer. Byrd J C and Bresalier R S. (2004) Cancer Metastasis Review January-June; 23(1-2):77-99.), wherein aberrant expression means that the receptor is no longer localized to the apical border of luminal cells but rather is uniformly distributed over the entire cell surface (Differential reactivity of a novel monoclonal antibody (DF3) with human malignant versus benign breast tumors. (1984) Kufe D, Inghirami G, Abe, M, Hayes D, Justi-wheeler H and Schlom J. Hybridoma, 3, 223-232). The greatest percentage of MUC1-positive cancers is in breast cancers where greater than 96% show aberrant MUC1 expression. Interestingly, in the adult female, breast tissue must undergo cyclic bursts of growth and apoptosis with each menstrual period and pregnancy. Thus it follows that breast tissue must maintain functional stem cell or at least progenitor cell populations throughout adult female life.
The identification of the growth factors and their receptors that drive the growth of cancer stem cells could provide the key to understanding how to grow and manipulate stem cells and progenitor cells for research, therapeutic and other uses.
MUC1 (mucin 1) is a transmembrane mucin glycoprotein that is expressed on a number of epithelial cell types (Molecular cloning and expression of the human tumor associated polymorphic epithelial mucin, PEM. Gendler Sj, Lancaster C A, Taylor-Papadimitriou J, Dhuig, T, Peat, N, Burchell, J, Pemberton, L, Lalani, E-N and Wilson D. (1990) J. Biol. Chem. 265, 15286-15293; Episialin, a carcinoma associated mucin, is generated by a polymorphic gene encoding splice variants with alternative amino termini. Ligtenberg M J L, Vos H L, Genissen, A M C and Hilkens J. (1990) J. Biol. Chem. 265, 15573-15578), on haematopoietic cells (Evaluation of MUC1 and EGP40 in Bone marrow and Peripheral Blood as a Marker for Occult breast cancer. (2001). Zhong X Y, Kaul S, Bastert G, Arch Gynecol Obstet 264:177-181), and on progenitor cells as well (Epithelial Progenitors in the Normal Human mammary Gland. Stingl J, Raouf A, Emerman J, and Eaves C. (2005). Journal of Mammary Gland Biology and Neoplasia, Vol. 10, No. 1, 49-59). The cell surface receptor MUC1 is present at the apical border of healthy epithelium, but is aberrantly expressed (spread over the entire cell surface) in a wide range of human solid tumors. It has been known for some time that the MUC1 receptor can be cleaved or “shed” from the cell surface. The MUC1 ectodomain is actually comprised of three distinct regions: 1) the tandem repeats; 2) an interchain binding region that self-aggregates; and 3) the portion of the receptor that remains attached to the cell surface following proteolysis, called PSMGFR herein. The portion of the MUC1 receptor that remains attached to the cell surface after cleavage, consisting primarily of PSMGFR, is the major growth factor receptor that mediates the growth of MUC1-positive cancer cells in vitro. Transfection of a mutant MUC1 receptor comprised of the intact transmembrane and cytoplasmic domains, but having an ectodomain that terminates at the end of the PSMGFR sequence, which has been shown to be a natural cleavage site that occurs on cancer cells, is sufficient to confer the ability of these cells to grow anchorage-independently—the test for transformation to a neoplastic state. This cleaved form of MUC1 is the predominant form of the MUC1 receptor on human cancerous tissue specimens.
In further detail, MUC1 comprises several regions termed herein as follows, recited in an order starting from the region closest to the cell surface and progressing away from the cell. The basic structure of the MUC1 receptor is illustrated in FIG. 1. The receptor, as illustrated comprises: 1) cytoplasmic tail; 2) transmembrane section; 3) MGFR; 4) IBR, 5) Unique Region, 6) repeats, and N-terminus region comprising a signal peptide. For a detailed description of MUC1 and its function in normal and tumor cells, see PCT/US2005/032821, which is incorporated by reference herein, in its entirety for its description of the function and activity of cleaved MUC1 on the cell surface.